Plasminogen-related growth factor and semaphorin receptors: A gene superfamily controlling invasive growth

Plasminogen-related growth factors (PRGFs), also known as 'scatter factors,' trigger a unique biological program leading to 'invasive growth.' This is a result of the integration of apparently independent biological responses including cell proliferation, cell survival, cell motility, invasion of extracellular matrices, and induction of cell polarity. Under physiological conditions, the coordinated execution of the underlying genetic programs leads to the formation of tubular structures by epithelial organs (the so-called branching morphogenesis). PRGF receptors are tyrosine kinases, encoded by a family of oncogenes: MET and RON. They feature unique signal transduction properties as their cytoplasmic tails contain a two-tyrosine multifunctional docking site that binds multiple SH2-containing intracellular signal transducers. Invasive growth results from the concomitant activation of Ras (growth), phosphatidylinositol 3-kinase ('scattering'), and signal transducer and activator of transcription (cell polarity and morphogenesis). We recently identified a new human gene family, encoding large transmembrane proteins, sex/plexins, sharing homologies with Met. These molecules are receptors for semaphorins, involved in axon guidance and cell-cell repulsion, a process reminiscent of scattering and invasive growth. Deregulated activation of PRGF or semaphorin ligands or receptors, by mutation or overexpression, confers to cancer cells invasive and metastatic properties.